Liu Jing, Malhotra Deepak, Ge Yan, Gunning William, Dworkin Lance, Gong Rujun
Division of Nephrology, Department of Medicine, Toledo, OH, United States.
Department of Pathology, The University of Toledo College of Medicine, Toledo, OH, United States.
Front Pharmacol. 2024 Jul 17;15:1430451. doi: 10.3389/fphar.2024.1430451. eCollection 2024.
Membranous nephropathy (MN) continues to be a leading cause of nephrotic syndrome in non-diabetic adults. As a unique subtype in the serology-based classification of MN, thrombospondin type 1 domain containing 7A (THSD7A)-associated MN has attracted increasing interest, because, unlike other autoantigens, THSD7A is also expressed in preclinical species, facilitating the study of its role in MN. A heterologous mouse model of THSD7A-associated MN was previously established using a proprietary in-house antibody that was unfortunately not available to the research community. Here, we developed a mouse model of THSD7A-associated MN by administering a commercially available antibody targeting the most N-terminal part of THSD7A. Our model was characterized by heavy proteinuria and pathological features of human MN without sex differences. Complement depletion with cobra venom factor only partially attenuated proteinuria and glomerular injury in this model, entailing that complement-independent pathomechanisms also contribute. Consistently, in primary podocytes, exposure to the anti-THSD7A antibody caused evident podocytopathic changes, including disruption of actin cytoskeleton integrity, podocyte hypermobility, oxidative stress, and apoptotic cell death. These signs of podocytopathy were preserved, albeit to a lesser extent, after complement inactivation, indicating autonomous podocyte injury. Furthermore, as the first FDA-approved treatment for primary MN, adrenocorticotropic hormone therapy with repository corticotropin injection (Purified Cortrophin Gel) appeared to be beneficial and significantly attenuated proteinuria and glomerular injury, suggesting that this model may be useful for developing novel treatments or understanding the pathogenesis of MN. Collectively, our model, based on the use of a commercially available anti-THSD7A antibody, will be an important tool for MN research.
膜性肾病（MN）仍然是非糖尿病成人肾病综合征的主要病因。作为基于血清学分类的MN独特亚型，含血小板反应蛋白1结构域7A（THSD7A）相关的MN已引起越来越多的关注，因为与其他自身抗原不同，THSD7A也在临床前物种中表达，便于研究其在MN中的作用。此前使用一种专有的内部抗体建立了THSD7A相关MN的异种小鼠模型，但遗憾的是研究界无法获得该抗体。在此，我们通过给予一种靶向THSD7A最N端部分的商业抗体，开发了一种THSD7A相关MN的小鼠模型。我们的模型以重度蛋白尿和人类MN的病理特征为特点，无性别差异。用眼镜蛇毒因子消耗补体仅部分减轻了该模型中的蛋白尿和肾小球损伤，这表明不依赖补体的发病机制也起作用。一致地，在原代足细胞中，暴露于抗THSD7A抗体导致明显的足细胞病变改变，包括肌动蛋白细胞骨架完整性破坏、足细胞过度运动、氧化应激和凋亡性细胞死亡。补体失活后，这些足细胞病变迹象得以保留，尽管程度较轻，表明足细胞自主损伤。此外，作为首个被美国食品药品监督管理局批准用于原发性MN的治疗方法，注射长效促肾上腺皮质激素（纯化促肾上腺皮质激素凝胶）进行促肾上腺皮质激素治疗似乎有益，并显著减轻了蛋白尿和肾小球损伤，这表明该模型可能有助于开发新的治疗方法或理解MN的发病机制。总的来说，我们基于使用商业抗THSD7A抗体的模型将成为MN研究的重要工具。
